Insulin resistant states such as NIDDM and obesity are characterized by a decrease in insulin stimulated glucose uptake. The insulin responsive glucose transporter GLUT 4, plays a major role in insulin stimulated glucose uptake in normal muscle and adipose cells. Although GLUT 4 is thought to be important in maintaining normal glucose homeostasis, it is not known whether alterations in GLUT 4 function will cause severe metabolic consequences. The goal of this proposal is to understand glucose metabolism in mice having no functional GLUT 4 and in mice where GLUT 4 is overexpressed in skeletal muscle. Two lines of genetically modified mice have been developed for this purpose. Mice which carry two disrupted alleles of GLUT 4 (Delta GLUT4/Delta GLUT4) have been established. The DeltaGLUT4/DeltaGLUT4 mice display post prandial hyperinsulinemia and represent a model for the study of insulin resistance similar to that seen in NIDDM and obesity. The other line of mice overexpressed GLUT 4 specifically in skeletal muscle (MLC GLUT4), the largest depot for post prandial glucose disposal. The MLC GLUT4 mice are hypersensitive to insulin. Mice genetically modified in GLUT4 will provide an animal paradigm for understanding glucose homeostasis, the response of glucose metabolism to insulin and the development of insulin resistance. Major questions which can be answered with the unique GLUT4 modified mice include: 1. Does the deficiency of the insulin responsive GLUT4 transporter cause diabetes? The rate of glucose clearance from the circulation can be compared in normal and DelatGLUT4/DeltaGLUT4 mice by euglycemic clamp and 2 deoxyglucose uptake experiments. Metabolites, hormones and enzyme activities of glucose homeostasis can be measured. 2. Does GLUT4 expression in skeletal muscle dictate whole body insulin sensitivity? The tissue patterns of muscle, adipose cell and liver enzyme expression can be compared in GLUT4 deficient and GLUT4 excess to provide unequivocal answers to the metabolic role of insulin responsive glucose transport effects. 3. Can the amount of GLUT4 expressed modify the response to nutritional or other stress? The insulin response of GLUT4 deficient and MLC GLUT4 mice can be compared in response to dietary stress (i.e. high fat or high carbohydrate diets) and to streptozotocin treatment to determine whether altered GLUT4 function will exacerbate or blunt the onset insulin resistance and obesity. 4. Does a tissue specific knockout of GLUT4 in skeletal muscle or adipose tissue have a different phenotype than a general GLUT4 knockout? The rate of glucose clearance from the blood of mice deficient in skeletal muscle or adipose tissue GLUT4 can be compared to Delta GLUT 4/Delta GLUT4 and normal mice to separate contributions of GLUT4 in skeletal muscle and adipose tissue to whole body insulin sensitivity.